Clozapine is a novel atypical antipsychotic compound which has shown superior efficacy both on clinical and extrapyramidal parameters in groups of treatment refractory schizophrenics. The exact nature of clozapine's particular biological and neurochemical mechanism of action has not been clarified. This proposal will investigate one aspect of clozapine's particular profile, its antiserotonergic (5HT2)property, in the treatment of refractory schizophrenics. We will study the behavioral and hormonal response to a serotonergic agonist probe (methyl-chloro-phenylpiperazine (m-CPP)) in these patients during a drug free phase prior to treatment with clozapine and then again after six weeks of treatment with clozapine. This research should allow us to investigate whether there is a subgroup of refractory schizophrenics who show central serotonergic hypersensitivity as manifested by specific hormonal and behavioral responses to m-CPP and whether clozapine treatment can attenuate these responses. This research will also allow us to establish potential predictors of response to clozapine and extend our knowledge regarding the clinical and pharmacological effects of clozapine.